ABCA3基因在先天性白内障合并小角膜发病中的作用机制研究

Cataract-microcornea syndrome (CCMC) is an autosomal dominant inherited disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Clinical findings include a corneal diameter inferior to 10 mm in both meridians, and an inherited cataract. There is no effective means of treatment for CCMC. There are still 60% CCMC patients with no known disease genes/loci identified. By whole exome sequencing analysis, we identified a new CCMC gene ABCA3 and the pathogenic mutations. In other five CCMC patients, we found another four ABCA3 mutations. The ABC family of transporters is a large family of related transmembrane proteins that bind and hydrolyze ATP to translocate a wide variety of substrates across biological membranes. In this project, we aim to investigate the role of ABCA3 in CCMC pathogenesis through the following experiments: (1) to screen gene mutations by enlarging CCMC samples in ABCA3 gene which has been identified in our previous study; (2) to investigate the effect of mutations on ABCA3 gene by cell biology research; (3) to investigate the regulating mechanism and their related signaling pathway;(4) to study the function of ABCA3 in vivo by using ABCA3 knock out mouse model. The purpose of this study is to examine the function of ABCA3 gene in CCMC and reveal the role of this gene in causing CCMC, and to clarify the pathophysiological mechanisms of CCMC.

白内障-小角膜综合征(CCMC)是以不同表型的白内障及角膜直径小于10mm为主要特征的一组遗传性致盲疾病。CCMC的防治手段有限，致病机制尚不明确；目前仍有60%的CCMC患者致病基因/位点待确定。前期通过全外显子组测序分析，我们在两个常染色体显性遗传的CCMC家系中发现了新CCMC致病基因ABCA3。ABCA3编码ATP结合盒转运蛋白超家族中一员，参与细胞膜内外各种分子的转运。本课题将围绕眼部生理和病理对ABCA3在CCMC致病中作用进行系统研究，主要包括：（1）扩大CCMC样本进行ABCA3基因的验证和新致病基因的鉴定；（2）体外细胞生物学研究突变体对该基因结构及功能的影响；（3）研究ABCA3基因分子调控机制及参与的信号通路；（4）通过角膜及晶状体特异性基因敲除小鼠模型，研究ABCA3基因缺失对角膜及晶状体形态和功能的影响。

白内障-小角膜综合征(CCMC)是一组严重的遗传性致盲疾病，CCMC的防治手段有限，致病机制尚不明确。本研究在收集（并将继续收集）的大量CCMC家系、散发病例及正常对照样本的基础上，扩大对ABCA3基因的验证并进行基因诊断产品的开发及应用，同时进行新致病基因的鉴定及相关生物学功能研究。首先设计了针对ABCA3基因全部外显子的19对引物，用直接测序法检测CCMC患者是否存在ABCA3基因的突变，并开发了一种用于检测先天性白内障-小角膜综合征的试剂盒；另外我们在对致病基因不明的CCMC家系及散发病例进行外显子组测序过程中，发现了新的CCMC的致病基因水通道蛋白5（AQP5），并从细胞生物学功能、分子调控机制及基因敲除及致病突变的基因敲入小鼠模型等体外体内多个层面开展了系列研究来探讨AQP5及其突变型的功能，本研究结果是通过功能研究确定AQP5其作为新的CCMC疾病致病基因的基础，将为CCMC疾病的发病机理及治疗研究等提供坚实的理论依据；我们还发现了小眼球-后极性白内障的致病基因脑垂体同源框3蛋白（PITX3）的新的SNP位点，并进行相关诊断产品开发及专利保护；研究组对临床先天性白内障及部分儿童严重并发症的临床资料及流行病学资料进行了统计分析，为先天性白内障的临床治疗提供一定参考资料。

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